Post-traumatic stress disorder (PTSD) occurs only in vulnerable individuals after exposure to severe traumatic events. This risk is due, in part, to 30-40% heritability of differential vulnerability or resilience. The previous period of this NIMH-supported project has involved a genome-wide association study (GWAS) involving over 8,000 subjects focusing on identifying genetic pathways associated with PTSD. Furthermore, our group has been at the lead in forming the Psychiatric GWAS Consortium (PGC) PTSD working group, which has now recruited sharing from approximately 20 investigators worldwide, which will result in GWAS samples for ~10,000 cases and ~25,000 controls by 2015. It is thus a very exciting time for discovering the underlying genetic risk factors contributing to PTSD. However, most successful GWAS analyses to date suggest that risk arises from multiple common variants of small effect size, such that cumulative polygenic risk may be the most powerful approach to understanding risk vs. resilience following trauma. Now that we are in the realm of large scale consortia genetics, multiple genes of small effect size are likely to be identified as contributingto PTSD. Approaches are needed to understand the function of these combined risk variants to inform our understanding of and therapeutic intervention for PTSD. We will first characterize variants that associate with PTSD from our own GWA studies and consortium- based data. We will then map these genetic markers onto gene regulation related to stress and relevant for fear processing followed by examination of physiological and neural intermediate phenotypes. We will accomplish this through the following specific aims: Aim 1 will identify GWAS candidates and polygenic risk score (PGRS) markers for PTSD from the GTP and PGC-PTSD cohorts. Aim 2 will examine the association of genetic variants and PGRS for PTSD with altered gene expression in the brain, in cells in response to stress, and in neuronally-differentiated iPSCs. Finally, Aim 3 will examine the association of specific genetic variants and PGRS for PTSD with neural intermediate phenotypes related to stress and fear physiology. We hypothesize that this approach will identify polygenic risk that is associated with PTSD and its intermediate phenotypes of stress and fear physiology and amygdala function. Furthermore, we hypothesize that these cumulative genetic risk factors will have identifiable molecular and electro-physiological signatures in inducible pluripotent stem cell (iPSC)-derived human neurons that point to molecular underpinnings of PTSD vulnerability vs. resilience. Understanding the genetic architecture of PTSD and its intermediate phenotypes will lead to neurobiological insight, enhanced prevention, and improved treatment of this debilitating and prevalent syndrome.